Enclomiphene citrate is an active pharmaceutical ingredient currently under evaluation in clinical phase III for the treatment of secondary hypergonadism. Moreover, it also could be potentially used for an adjuvant therapy in hypogonadal men with Type 2 diabetes.
Enclomiphene citrate of formula (I):

has chemical name of Ethanamine, 2-[4-[(1E)-2-chloro-1,2-diphenyl ethenyl]phenoxy]-N,N-diethyl-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1); has CAS RN. 7599-79-3, and it is also named trans-Clomiphene monocitrate, E-Clomiphene citrate or Enclomiphene monocitrate.
Enclomiphene is component of Clomiphene, an active pharmaceutical ingredient, having chemical name Ethanamine, 2-[4-(2-chloro-1,2-diphenylethenyl)phenoxy]-N,N-diethyl, since Clomiphene is a mixture of the geometric isomers trans-Clomiphene (i.e. Enclomiphene) and cis-Clomiphene.
The U.S. Pat. No. 3,848,030, in examples 31 and 32, discloses a process for the resolution of the geometric isomers of Clomiphene through the preparation of salts with racemic binaphthyl-phosphoric acid.
In the later publication Acta Cryst. (1976), B32, pag. 291-293, the actual geometric isomery has been definitely established by single crystal X-Ray diffraction.
Finally, in the publication “Analytical profiles of drug substances and excipients”, vol. 25, (1998), pag. 85-121, in particular at pag. 99, it is stated that prior to 1976 the cis stereochemistry was wrongly assigned to the trans-isomer of Clomiphene (E-Chlomiphene or Enclomiphene), and only after the above publication on Acta Cryst. the correct geometric isomery has been definitively assigned.
These observations in the prior art have been confirmed by our experimentation. In particular, repeating the experiment 31 of U.S. Pat. No. 3,848,030, the trans-Clomiphene salt with racemic binaphthyl-phosphoric acid was isolated and not the salt with cis-Clomiphene as stated in said patent, as confirmed by 2D H-NMR analysis (NOESY experiment). Thus, Example 31 of U.S. Pat. No. 3,848,030, provides, at the end, Enclomiphene citrate, crystallized from a mixture of ethyl ether and ethanol, having a m.p. of 133-135° C. Example 32, instead provided Cis-Clomiphene citrate, crystallized from a mixture of ethyl ether and ethanol, having a m.p. of 120-126° C.
Thus, with the aim of preparing Enclomiphene citrate, whole experiment 31 of U.S. Pat. No. 3,848,030 has been reworked also carrying out the crystallization of the product form a mixture of ethyl ether and ethanol, hence providing a not crystalline solid with two DSC peaks respectively at 114° C. and 188° C., although the starting material used for the reworking example was quite a pure substance (HPLC Analysis (A/A %) is 98.95% of Enclomiphene), and having a substantially the same chemical purity of that used in the prior art experiment (m.p. of our Enclomiphene BPA salt was 218° C. versus 220-222° C. of the prior art Enclomiphene BPA salt of Example 31).
The U.S. Pat. No. 2,914,563, in example 3, discloses a process for the preparation of trans-Clomiphene citrate, containing from 30% to 50% of cis-Clomiphene, as citrate, by reaction of 1-p-(β-diethylaminoethoxy)phenyl]-1,2-diphenylethylene hydrochloride with N-chlorosuccinimmide in dry chloroform under reflux.
Khimiko-Farmatsevticheskii Zhurnal (1984), 18(11), 1318-24 English translation in the review Pharmaceutical Chemistry Journal November 1984, Volume 18, Issue 11, pag. 758-764 (Title: Synthesis and biological study of the cis- and trans-isomers of Clomiphene citrate and some intermediates of its synthesis) discloses the trans-isomer of Clomiphene citrate, i.e. Enclomiphene citrate, characterized by:
1H-NMR (MeOD) d 7.4-6.7 (m, 14H); 4.27 (t, 2H, —OCH2); 3.51 (t, 2H, CH2—N); 3.28 (q, 4H, 2×N—CH2)); 2.73 (2H); 2.78 (2H); 1.31 (t, 6H, 2×N—C—CH3)) Melting point: 138-139° C. (98% purity by GLC);
IR spectrum, v cm−1 (suspension in mineral oil): 3640, 3430, 1720, 1710 (citrate), 1600-1555 (broad band, stilbene system); 750.
UV spectrum: Å max=243 nm, ε 21,800 and Å max 300 nm, ε 11,400.
These prior art methods for the preparation of Enclomiphene citrate do not allow the preparation of Enclomiphene citrate having needle shaped crystal habit, indeed the crystallization by means of a mixture of ethyl ether and ethanol does not provide a crystalline solid having needle crystals.
Moreover, Enclomiphene citrate was described in literature with different melting points, in particular, 133-135° C. and 138-139° C. Said solid forms of Enclomiphene citrate fail to comply with stabilities studies and furthermore show relatively poor solubility in water either in neutral or acid pH.
Furthermore, the prior art methods have the drawbacks related to the poor reproducibility of the process and of the solid form thus obtained.